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Names | |
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IUPAC name
(2Z,4E,9Z,23Z,25Z)-12,28-bis[(E)-3-hydroxy-2-methylhex-4-en-2-yl]-20-methoxy-7,13,17,29,33-pentaoxa-34,35-diazatetracyclo[29.2.1.115,18.06,8]pentatriaconta-1(34),2,4,9,15,18(35),21,23,25,31-decaene-14,30-dione
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Other names
Disorazole; Disorazol A
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Identifiers | |
3D model (
JSmol)
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ChemSpider |
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PubChem
CID
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Properties | |
C43H54N2O10 | |
Molar mass | 758.909 g·mol−1 |
Except where otherwise noted, data are given for materials in their
standard state (at 25 °C [77 °F], 100 kPa).
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Disorazol, a cyclic polyketide synthesized by the bacterium Sorangium cellulosum So ce12, was first detected and isolated in 1994. [1] Its chemical structure consists of a macrocyclic ring and two oxazole rings. [1] Disorazol A has been demonstrated to exhibit anti-fungi activities, but it was not active against yeasts. [1] In addition, this substance demonstrates potent anti-cancer characteristics at exceptionally low picomolar levels by obstructing the mechanism of tubulin assembly and triggering the disruption of microtubules. As a result, these impacts lead to the initiation of cell apoptosis. [2] However, disorazols cannot be directly used as drugs in the clinic due to its extremely high cytotoxicity and instability. [2] Thus, chemical and biosynthetic synthesis pathways were designed to synthesize unnatural derivatives of disorazol in hope of reducing its cytotoxicity without decreasing its anti-cancer potency. [2]
Four synthetic genes, disABCD, have been identified and documented as contributors to the biosynthesis of disorazol. The disABC genes encode hybrid trans-AT type polyketide synthase (PKS) megaenzymes, while the disD gene encodes an additional acyl transferase protein and an enoylreductase (ER). [2] Notably, the ER encoded in the disD gene was not involved in the biosynthesis pathway of disorazol. [2]
Generally, 10 synthetic modules were involved in the biosynthesis pathway of disorazol. The formation of half of the disorazol bis-lactone core involves the utilization of seven malonyl-CoA molecules and one serine molecule as extender units. [3] Subsequently, the dimerization or cyclization of two polyketide monomers takes place within the thioesterase (TE) domain located in module 10, leading to the synthesis of disorazol. [3] Furthermore, the release of the final product is facilitated by module 8, 9, and 10. [3] The process of PKS monomer dimerization in the biosynthesis pathway of disorazol exhibits an unconventional nature. [2]